IGFBP5
Insulin-like growth factor-binding protein 5 precursor (IBP-5) (IGF-binding protein 5) (IGFBP-5) [IBP5]
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Idiopathic pulmonary fibrosis (IPF) pathogenesis has been postulated to involve a variety of mechanisms associated with the aging process, including loss of protein homeostasis (proteostasis). Heat shock proteins are cellular chaperones that serve a number of vital maintenance and repair functions, including the regulation of proteostasis. Previously published data have implicated heat shock protein 70 (Hsp70) in the development of pulmonary fibrosis in animal models. We sought to identify alterations in Hsp70 expression in IPF lung. Hsp70 mRNA and protein were decreased in primary fibroblasts cultured from IPF versus normal donor lung tissue. In addition to cultured fibroblasts, Hsp70 expression was decreased in intact IPF lung, a stressed environment in which upregulation of protective heat shock proteins would be anticipated. In support of a mechanistic association between decreased Hsp70 and fibrosis, cultured primary lung fibroblasts deficient in Hsp70 secreted increased extracellular matrix proteins. Treatment of primary normal human lung fibroblasts [i]in vitro[/i] with either of the profibrotic molecules IGFBP5 (insulin-like growth factor-binding protein 5) or transforming growth factor-β1 downregulated Hsp70, suggesting Hsp70 is a downstream target in the fibrotic cascade. Hsp70-knockout mice subjected to an inhalational bleomycin model of pulmonary fibrosis demonstrated accelerated fibrosis versus wild-type control animals. We therefore conclude that reduced Hsp70 protein contributes to fibrosis and that interventions aimed at restoring normal expression of Hsp70 represent a novel therapeutic strategy for pulmonary fibrosis.
MeSH Terms
- Aging
- Animals
- Bleomycin
- Fibroblasts
- HSP70 Heat-Shock Proteins
- HSP72 Heat-Shock Proteins
- Humans
- Idiopathic Pulmonary Fibrosis
- Insulin-Like Growth Factor Binding Protein 5
- Intracellular Space
- Lung
- Mice
- Phenotype
- Transforming Growth Factor beta1
Keywords
- heat shock protein 70
- idiopathic pulmonary fibrosis
- proteostasis
- transforming growth factor-β
Insulin-like growth factor-1 (IGF-1) regulates protein synthesis and cell cycle kinetics. Given that aging is associated with anabolic resistance, we sought to determine if the attenuated exercise-induced satellite cell (SC) expression in older muscle is associated with a blunted IGF-1 response. SC expression (Pax7 cells) and protein (Western blot) and mRNA (RT-PCR) expression of IGF-1 splice variants and ubiquitous (IGFBP4) and muscle-specific (IGFBP3 and -5) IGF-1 binding proteins were measured in skeletal muscle of young (Y: 22 ± 2, n = 7) and older (O: 70 ± 2, n = 7) adults up to 48 h after an acute bout of resistance exercise. SC expression was greater in Y compared to O (age; P < 0.01) and increased (interaction; P < 0.05) by 24 h after exercise in Y only. IGF-1Ea and IGF-1Eb mRNA tended to be greater in O (age; P < 0.06-0.09). IGF-1Eb mRNA increased at 48 h (time; P < 0.05), whereas IGF-1Ec mRNA increased (interaction; P < 0.05) at 24 and 48 h in O only. IGF binding protein (IGFBP)4 mRNA was greater (age; P < 0.01) in O with the increase at 24 h and 48 h (time; P < 0.01) primarily driven by changes in O (interaction; P < 0.01). Despite IGFBP3 mRNA being greater in O (age; P < 0.01) and increasing at 48 h (time; P < 0.01), there was no effect of age or exercise on IGFBP3 protein expression. In contrast, IGFBP5 mRNA was greater (age; P < 0.01) despite IGFBP5 protein expression being lower (age; P < 0.01) in O compared to Y. The greater muscle-specific expression of IGF-1 family members with a blunted post-exercise SC expression may be a compensatory attempt to rescue age-related anabolic resistance.
MeSH Terms
- Aged
- Aging
- Exercise
- Humans
- Insulin-Like Growth Factor Binding Proteins
- Insulin-Like Growth Factor I
- Male
- Satellite Cells, Skeletal Muscle
- Young Adult
Keywords
- Exercise
- Hypertrophy
- Muscle protein synthesis
- Sarcopenia
- Satellite cells
We propose here material-induced senescence (MIS) as a new therapeutic concept that limits cancer progression by stable cell cycle arrest. This study examined for the first time the effect of material fluidity on cellular senescence in lung carcinoma using poly(ε-caprolactone-[i]co[/i]-D, L-lactide) (P(CL-[i]co[/i]-DLLA)) with tunable elasticity and fluidity. The fluidity was varied by chemically crosslinking the polymer networks: the crosslinked P(CL-[i]co[/i]-DLLA) shows solid-like properties with a stiffness of 260 kPa, while the non-crosslinked polymer exists in a quasi-liquid state with loss and storage moduli of 33 kPa and 11 kPa, respectively. We found that cancer cells growing on the non-crosslinked, fluidic substrate undergo a non-apoptotic form of cell death and the cell cycle was accumulated in a G0/G1 phase. Next, we investigated the expression of biomarkers that are associated with cancer pathways. The cancer cells on the fluidic substrate expressed several biomarkers associated with senescence such as insulin-like growth factor binding protein 5 (IGFBP5). This result indicates that when cancer cells sense fluidity in their surroundings, the cells express IGFBP5, which in turn triggers the expression of tumor suppressor protein 53 and initiates cell cycle arrest at the G1 phase followed by cellular senescence. Furthermore, the cancer cells on the fluidic substrate maintained their epithelial phenotype, suggesting that the cancer cells do not undergo epithelial to mesenchymal transition. By considering these results as the fundamental information for MIS, our system could be applied to induce senescence in treatment-resistant cancers such as metastatic cancer or cancer stem cells.
MeSH Terms
- Carrier Proteins
- Cell Cycle
- Cell Death
- Cell Line, Tumor
- Cellular Senescence
- Elasticity
- Humans
- Lung Neoplasms
- Polyesters
- Tumor Suppressor Protein p53
Keywords
- fluidity
- insulin-like growth factor binding protein 5
- p(ε-caprolactone)
- senescence
- tumor suppressor protein 53.
Ionizing radiation has been recognized to increase the risk of cardiovascular diseases (CVD). However, there is no consensus concerning the dose-risk relationship for low radiation doses and a mechanistic understanding of low dose effects is needed. Previously, human umbilical vein endothelial cells (HUVEC) were exposed to chronic low dose rate radiation (1.4 and 4.1 mGy/h) during one, three and six weeks which resulted in premature senescence in cells exposed to 4.1 mGy/h. To gain more insight into the underlying signaling pathways, we analyzed gene expression changes in these cells using microarray technology. The obtained data were analyzed in a dual approach, combining single gene expression analysis and Gene Set Enrichment Analysis. An early stress response was observed after one week of exposure to 4.1 mGy/h which was replaced by a more inflammation-related expression profile after three weeks and onwards. This early stress response may trigger the radiation-induced premature senescence previously observed in HUVEC irradiated with 4.1 mGy/h. A dedicated analysis pointed to the involvement of insulin-like growth factor binding protein 5 (IGFBP5) signaling in radiation-induced premature senescence. Our findings motivate further research on the shape of the dose-response and the dose rate effect for radiation-induced vascular senescence.
MeSH Terms
- Cellular Senescence
- Dose-Response Relationship, Radiation
- Gene Expression Profiling
- Human Umbilical Vein Endothelial Cells
- Humans
- Insulin-Like Growth Factor Binding Protein 5
- Signal Transduction
- Time Factors
- Transcriptome
Keywords
- Gene expression
- chronic low dose rate ionizing radiation
- endothelial cells
- senescence